Linagliptin is a DPP-4 inhibitor developed by Boehringer Ingelheim for the treatment of type II diabetes [Wikipedia]. Two pharmacological characteristics that sets linagliptin apart from other DPP-4 inhibitors is that it has a non-linear pharmacokinetic profile and is not primarily eliminated by the renal system. FDA approved on May 2, 2011. In comparison, sitagliptin, saxagliptin, and vildagliptin have an IC50 of 19, 50, and 62 nM respectively. A dose of 2.5 and 5 mg reduces the activity of DPP-4 by 72.7% and 86.1% from baseline respectively in healthy male subjects. In diabetes patients, a dose of 5 and 10 mg inhibits >90% of DPP-4. Linagliptin is also selectively inhibited DPP-4 as indicated by the lack of DPP-8 or DPP-9 inhibition at therapeutic exposures in vitro.
Mechanism of Action of Linagliptin
Linagliptin belongs to a class of drugs called DPP-4 inhibitors. DPP-4 inhibitors prevent the hormone incretin from being degraded, allowing insulin to be released from the pancreatic beta cells. While incretin remains in the blood stream, the pancreas is stimulated to produce more insulin. Meanwhile, glucagon release from the pancreas is staggered, preventing glucose level increase. In other words, linagliptin, along with diet and exercise, can help the body produce more insulin and lower blood glucose. Managing blood sugar can mean a lower HbA1c, an index for glycemia control that theoretically correlates with glucose level in the blood.
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Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta-cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in a reduction in hepatic glucose output.
Indications of Linagliptin
- Type 2 Diabetes Mellitus
- The drug can effectively reduce blood sugar
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Linagliptin is used for the management of type 2 diabetes mellitus.
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Trajenta is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control as monotherapy
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when metformin is inappropriate due to intolerance or contraindicated due to renal impairment.
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Combination therapy in combination with other medicinal products for the treatment of diabetes, including insulin, when these do not provide adequate glycaemic control.
Contra-Indications of Linagliptin
- Low blood sugar
- Pituitary hormone deficiency
- Decreased Function of the Adrenal Gland
- Inadequate Vitamin B12
- Excess Body Acid
- Extreme Loss of Body Water
- Habit of Drinking Too Much Alcohol
- Alcohol Intoxication
- Heart Attack
- Suddenly serious symptoms of heart failure
- Liver Problems
- Recent operation
- Fever
- Shock
- Severe Vomiting
- Severe Diarrhea
- Serious Lack of Oxygen in the Blood
- Weakened Patient
- Injury
- Sepsis Syndrome
- X-Ray Study with Intravenous Iodine Contrast Agent
- Chronic kidney disease stage 3B (moderate)
- Chronic kidney disease stage 4 (severe)
- Chronic kidney disease stage 5 (failure)
- Kidney disease with a likely reduction in kidney function
- Pancreatitis
Dosage of Linagliptin
Strengths: 5 mg
Diabetes Type 2
- Recommended dose: 5 mg orally once a day
Side Effects of Linagliptin
Most common
- physical weakness (asthenia)
- diarrhea
- gas (flatulence)
- symptoms of weakness, muscle pain (myalgia)
- upper respiratory tract infection
- low blood sugar (hypoglycemia)
- abdominal pain (GI complaints), lactic acidosis (rare)
- low blood levels of vitamin B-12
- nausea,vomiting
- chest discomfort
- chills, dizziness
- bloating/abdominal distention
- constipation
- heartburn
More common
- Abdominal or stomach discomfort
- cough or hoarseness
- decreased appetite
- diarrhea
- fast or shallow breathing
- fever or chills
- general feeling of discomfort
- lower back or side pain
- muscle pain or cramping
- painful or difficult urination
Less common
- Abnormal stools
- bad, unusual, or unpleasant (after) taste
- change in taste
- difficulty with moving
- discoloration of the fingernails or toenails
- flu-like symptoms
- joint pain
- rash
- runny nose
- sneezing
- stuffy nose
- swollen joints
Drug Interactions of Linagliptin
Linagliptin may interact with following drugs, supplements & may decrease the efficacy of the drug
- angiotensin-converting enzyme inhibitors (ACEIs; captopril, enarapril,ramipril)
- alcohol
- antipsychotic medications (e.g., chlorpromazine, haloperidol, olanzapine,
- birth control pills
- bupropion
- atorvastatin
- atypical antipsychotics (e.g., aripiprazole, clozapine, olanzapine; quetiapine, risperidone)
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- barbiturates (e.g., pentobarbital, phenobarbital)
- crizotinib
- cyclosporine
- cyproterone
- dabrafenib
- corticosteroids (e.g., dexamethasone, prednisone)
- diabetic drugs (e.g., glyburide, insulin, repaglinide, sitagliptin)
- diuretics (e.g., furosemide, hydrochlorothiazide)
- HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
- phenytoin
- quinolone antibiotics (e.g., levofloxacin, moxifloxacin)
- selective serotonin reuptake inhibitors (SSRIs; citalopram, fluoxetine, sertraline paroxetine,
- trimethoprim
- vancomycin
- verapamil
- warfarin
Pregnancy & Lactation of Linagliptin
FDA Pregnancy Category B
Pregnancy
This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.
Lactation
It is not known if linagliptin passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.
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